Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma. Tumor angiogenesis, the formation of new blood vessels and their permeability is primarily regulated by (tumor-derived) vascular endothelial growth factor (VEGF), which acts via at least two different receptors: VEGF-R1 (fms-like tyrosine kinase, Flt-1); and VEGF-R2 (kinase domain region, KDR/fetal liver kinase-1, Flk-1). The VEGF KDR receptor is highly specific for vascular endothelial cells (for review, see: Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEB J. 1999, 13, 9).
VEGF, and more specifically VEGF-A, exists in the human species in three isoforms (through alternative splicing), which are named according to the number of amino acid residues: VEGF 121, VEGF 165 and VEGF 189. These isoforms have distinct functional properties in terms of heparin binding and diffusibility. A related factor, placenta growth factor (PIGF), only binds VEGF-R1/Flt-1.
VEGF expression is induced by hypoxia (Shweiki et al. Nature 1992, 359, 843), as well as by a variety of cytokines and growth factors, such as interleukin-1, interleukin-6, epidermal growth factor and transforming growth factor-α and β.
The membrane-bound VEGF receptors occur on the surface of activated endothelial cells and possess an intracellular tyrosine-kinase domain, which is necessary for intracellular signal transduction. It is thought that the VEGF dimer induces, upon binding, a dimerization of two receptor molecules, leading to autophosphorylation of the intracellular portion of the receptors and subsequent binding of SH2-containing proteins. Subsequent phosphorylation (activation) of phospholipase C, phosphatidylinositol-3 kinase and Ras GTPase-activating protein (GAP) has been demonstrated.
A large number of human tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF released by tumor cells stimulates the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner and through the improved blood supply, accelerate tumor growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo is shown in studies in which VEGF expression or VEGF activity was inhibited. This was achieved with anti-VEGF antibodies, with dominant-negative VEGFR-2 mutants which inhibited signal transduction, and with antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumor cell lines in vivo as a result of inhibited tumor angiogenesis.
Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: 1) Inhibition of the growth of vessels, especially capillaries, into vascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between cell death and proliferation; 2) Prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and 3) Inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels.
The present invention is based on the discovery of compounds that surprisingly inhibit the effect of VEGF receptor tyrosine kinase, a property of value in the treatment of disease states associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune disease, acute inflammation, excessive scarformation and adhesions, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation as well as other angiogenesis and its related diseases.
Examples of anthranilic acid and nicotinic acid derivatives that are similar in structure to those of the present application are disclosed in the following patent applications: WO 02066470, WO 02068406, WO 0027819, WO 0027820, WO 0155114, WO 0185671, WO 0185691 and WO 0185715.